Recently, consumption of MDMA or 'ecstasy' has been rising among young women. Consequently, there is a substantial risk of exposure among women who are, or become, pregnant while abusing MDMA. The few prenatal MDMA animal studies conducted have failed to demonstrate any lasting neurobiological alterations from prenatal MDMA exposure. Alternative models utilizing neonatal rather than prenatal MDMA exposures have demonstrated alterations in serotonergic systems as well as learning decrements, but the validity of neonatal rodent models is questionable as they model 3rd trimester development (pregnant women use MDMA primarily in the 1st trimester). We have recently demonstrated that prenatal MDMA exposure from days 14-20 induced long lasting changes in DA metabolism at postnatal days (P) 3, 7 and 21 as well as increased DA fiber density when examined at P21. At P21 DA fiber density in prenatally MDMA exposed rats was increased in the frontal cortex by 502% with smaller but significant increases in striatum, nucleus accumbens and the lateral septum. This was the first published report that prenatal MDMA can result in long-lasting brain alterations. We propose to longitudinally examine the persistence of these neurochemical and histological changes in prenatally MDMA exposed rats as well as examine changes in DAT and trophic factors that may provide a mechanism for the observed changes in DA neurochemistry and TH fiber density. Stereologic cell counts of TH+ neurons in the SN and VTA revealed no changes in cell number, suggesting that the increased fiber density is a result of collateral sprouting rather than increased cell numbers. We have also demonstrated increased fiber degeneration at P2 (silver stain) followed by signals for neurite collateral sprouting at P7 (netrin-l/ephrin-b2). Bolte-Taylor et al (1998) [5] demonstrated that lesions of the Raphe result in 5-HT fiber loss in the cortex followed by a proliferation of DA fiber collaterals. Based upon these findings we hypothesize that MDMA induced losses of 5-HT fibers as a result of prenatal MDMA exposure is the mechanism behind increased TH fiber density in the frontal cortex as well as other structures. Furthermore, we will examine whether our prenatally MDMA-exposed, DA hyperinnervated rats are more sensitive to the neurotoxic potential of methamphetamine, a known DA neurotoxin. Ultimately, these studies should provide us with specific answers with respect to the importance of 5-HT fiber degeneration, monoamine fiber competition, trophic factors and sprouting cues on our observed changes in the brain of MDMA exposed neonates and whether such subjects are at greater risk for damage from environmental neurotoxic insults as they mature. [unreadable] [unreadable]